Selective hydrogenation pregnadien-



United States Patent 3,125,588 SELECTIVE HYDROGENATION PREGNADIEL OLONE AND ITS ESTERS AT THE C -C POSITION Peter Edward Macey and Peter Oxley, Nottingham, England, assignors to Boots Pure Drug Company Limited, Nottingham, England, a British company No Drawing. Filed Oct. 15, 1962, Ser. No. 230,682 Claims priority, application Great Britain Oct. 31, 1961 6 Claims. (Cl. 260-3914) This invention relates to the hydrogenation of steroids. In particular it relates to the selective hydrogenation of steroids containing a A double bond.

A number of stages in various processes for producing corticosteroids use intermediates containing a A double bond requiring hydrogenation at C and C Included among such intermediates are A 1pregnad-ien-3-beta-ol- 20-one and its esters such as pregnadienolone acetate. These hydrogenations are usually con-trolled by periodic checking at short intervals of the amount of hydrogen absorbed and ceasing to hydrogenate when the required volume of hydrogen has been absorbed. Not only is continuous supervision of the reaction necessitated but the product of hydrogenation needs careful purification from lay-products which are produced \by a certain degree of hydrogenation at other groups which are less easily reduced.

We have now discovered that when such compounds containing a A double bond are hydrogenated in solution in benzene or toluene, either with or without the addition of a secondary solvent, hydrogenation proceeds to completion vat C and C without simultaneous attack at the A double bond.

According to the present invention the-re is provided a process \for the selective hydrogenation of steroids at the C C position whereby a A5116 steroid is hydrogenated in the presence of benzene or toluene.

The starting material may be any A steroid which is otherwise stable under the conditions of the hydro-gen ation but the reaction is particularly applicable to pregnadienes.

The starting material may be dissolved in pure benzene or toluene in which solubility is excellent. It is not necessary, however, to employ a single solvent and mixtures may be found to :be advantageous. For example, we have found that an excellent product may be recovered from the reduction of pregnadienolone acetate in a mixture of ethyl acetate and toluene. The speed of hydrogenation is faster than with toluene alone but more solvent has to be used because of the lower solubility of pregnadienolone acetate in ethyl acetate.

Hydrogenation according to the invention may be carried out at atmospheric pressure or at higher pressures. In the laboratory using glass apparatus atmospheric pressures are generally used but on the larger scale we have found that higher pressures give rapid, efficient hydrogcnations. We normally hydrogenate at pressures up to 50 lb./sq. in., preferably at about 30 lb./ sq. in.

The temperature of hydrogenation is not critical and may vary considerably. We normally hydrogenate at or slightly higher than room temperature but owing to the reaction being exothermic, a final temperature of 50-55" C. is reached during hydrogenation under pressure.

The catalyst may :be palladium on a suitable carrier such as alumina, barium sulphate, zinc oxide or charcoal. We have found that 5% palladised alumina gives very satisfactory results and that 100 g. of steroid may be etficiently hydrogenated using 1-10 g. of catalyst. It is highly important, as with all catalytic reactions of this nature that the solvents used in the reaction be of high purity [and free of compounds containing elements such as sulphur which might poison the catalyst and inhibit the hydrogenation.

The following non-limiting examples illustrate the invention.

Example 1 Pregnadienolone acetate (10 g.) dissolved in toluene (50 ml.) was hydrogenated in a shaken glass hydrogenator at atmospheric temperature and pressure in the presence of 1 g. of 5% palladised alumina. The uptake of hydrogen was measured at intervals to [indicate the process of therhydrogenation. The calculated volume of hydrogen required for reduction of the A double bond was 675 ml. at 20 C./760 mm. At the end of the hydrogenation the catalyst was filtered off and washed and the filtrates evaporated to dryness. The melting point of the crude product was within the range l44- l48 C. indicating good quality pregnenolone acetate, without further purification. The following three results show the automatic cessation of hydrogenation atter saturation of the A bond to roduce a relatively pure pregnenolone acetate.

TOLUENE 50 ML.

Hours. Crude M.P.: Lil-148 0.

By way of comparison similar hydrogenatic us were carried out in the following solvents commonly used in the hydrogenation of steroids. In each case hydrogenation continued (at a lower rate) after the saturation of the A double bond.

ETHYL ACETATE ML.) 24 0., 702 MM.

Time (1111115.) 2 7 12 17 27 42 57 72 87 1s l-huptake (1111.) 380 500 650 690 700 710 720 740 1,010

TETRAHYDROFURAN (100 ML.), 20 0., 758 MM.

Time (ruins) 5 10 15 20 25 35 100 235 450 24 H1uptake(1n1.) 230 430 570 040 660 670 690 700 750 790 1, 080

AOETIC ACID (100 ML.), 22 0., 772 MM.

Time (ruins) 2 4 0 8 10 30 60 100 H1 uptake (ml.) 280 520 650 690 700 750 790 840 950 Hours.

Example 2 Time (mins.) 24

50 H1 uptake (m1.) 340 Crude M.P.: mas-147.5 o.

Example 3 Pregnadienolone acetate (10 g.) was dissolved in a mixture of ethyl acetate (100 ml.) and toluene (20 ml.) and hydrogenated in the presence of palladised alumine (1 g.) as described in Example 1 at 24 C. and 770 mm.

Time (mins) 5 15 20 30 50 60 80 105 18 Hz uptake (ml.) 100 250 330 430 580 630 660 670 680 1 Hours. Crude M.P.: 143147 C.

Example 4 Hydrogenations of 'pregnadienolone acetate g.) in toluene (75 ml.) were carried out as described in EX- ample 1 but using as catalyst 10% palladised charcoal e)- TOLUENE (75 ML.)

[(1') 20 0., 753 mm. Crude M.P.: 145147 0.]

Time (mins) 5 10 25 55 70 85 130 180 1 8 Hz uptake (ml 70 130 290 530 610 660 700 700 (390 [(ii) 23 C., 755 mm. Crude Ml; 144-147" (1.]

Time (mins.) 5 40 150 250 1 20 Hz uptake (1nl.) 150 660 700 710 700 1 Hours.

By way of comparison similar hydrogenations were carried out in methanol and ethyl acetate, both solvents being commonly used in steroid hydrogenations. In both cases a low melting, insufiiciently pure crude product was obtained.

METHANOL (300 1111.), 20.5 0., 748 mm.

1 Hours.

rude M.P.:132140 C,

Example 5 Time (mills) 0 10 2O 30 40 H2 uptake (cu. ft.). H. 0 200 400 550 600 600 Temperature, C 27 36 45 51 51 50 We claim:

1. A process for the selective hydrogenation at the 16-l7 position of a compound selected from the group consisting of A -pregnadien-3B-oLZO-one and its lower alkanoic acyl esters which comprises subjecting such compound to hydrogenation in the presence of a solvent selected from the group consisting of benzene and toluene.

2. A process for the selective hydrogenation at the 16-l7 position of a compound selected from the group consisting of A -pregnadien-Bfi-ol-ZO-one and its lower alkanoic acyl esters which comprises subjecting such compound to catalytic hydrogenation in the presence of a solvent selected from the group consisting of benzene and toluene in the presence of a. supported palladium catalyst at a pressure between atmospheric and about 50 lb./sq. in.

3. The process of claim 2 in which ethyl acetate is also present as solvent during such hydrogenation.

4. The process of claim 2 in which said supported palladium catalyst is palladized alumina.

5. The process of claim 2 in which said supported palladium catalyst is palladized charcoal.

6. A process \for the production of A -pregnen-3fi-ol- 20-one acetate which comprises hydrogenating a solution of A pregnadicn-3fl-0l-20-one acetate in toluene at a pressure of about 30 lb./ sq. in. in the presence of about 1 g. of a 5% palladized alumina catalyst per 25 g. of steroid.

No references cited, 

1. A PROCESS FOR THE SELECTIVE HYDROGENATION AT THE 16-17 POSITION OF A COMPOUND SELECTED FROM THE GROUP CONSISTING OF $5,16-PREGNADIEN-3B-OL-20-ONE AND ITS LOWER ALKANOIC ACYL ESTERS WHICH COMPRISES SUBJECTING SUCH COMPOUND TO HYDROGENATION IN THE PRESENCE OF A SOLVENT SELECTED FROM THE GROUP CONSISTING OF BENZENE AND TOLUENE. 